Modeling the Role of Follicular Dendritic Cells in Accelerating HIV Colonization of Lymphoid Tissues

Introduction: : Following initial infection, HIV spreads to regional lymph nodes within 3–6 days, and systemic dissemination occurs within 6–25 days. However, current mathematical models of HIV infection often fail to replicate this timeline, typically predicting a ~30-day delay in viral appearance within both blood and lymph node. We hypothesize that this discrepancy arises from the omission of follicular dendritic cells (FDCs), which are known to facilitate HIV import and long-term retention within lymphoid tissues, particularly in B cell follicles. To address this, we extended the HIV infection model by incorporating FDCs into a partial differential equation (PDE) framework. Specifically, we introduced a new reaction term to capture the transfer of free virus from lymph to FDCs. The model was solved using the finite volume method (FVM) on a tetrahedral mesh of a 3D-reconstructed murine lymph node. Simulation results support our hypothesis, demonstrating that FDCs accelerate HIV colonization of the lymph node by trapping virus directly from lymphatic fluid.

Materials and

Methods: : In this study, we extended the HIV infection model by adding a new compartment for virus captured by and retained on FDCs. The system is governed by coupled reaction-diffusion partial differential equations that describe the spatial and temporal evolution of uninfected CD4+ T cells, infected CD4+ T cells, free virus, and virus captured by FDCs. These equations include terms for T cell recruitment and death, infection by free virus, viral replication, and clearance. The virus–FDC interaction is represented through a linear capture term, calibrated using literature-based estimates of viral half-life on FDC networks and lymphatic fluid flow rates.

The model was implemented on a three-dimensional tetrahedral mesh representing a murine lymph node lobule. The geometry was reconstructed from imaging data, and discretization was performed using the finite volume method to ensure conservation of mass across compartments. Structures representing blood vessels were introduced independently and overlaid onto the lobule geometry. FDCs were modeled separately as discrete point clouds, positioned within the outer cortex of the lobule in accordance with their biological localization in B cell follicles. These FDCs serve as reservoirs by capturing and retaining free virus from lymphatic fluid. To ensure precise spatial alignment among the lymph node, vasculature, and FDCs, the Iterative Closest Point (ICP) algorithm was used.

This modeling framework provides a mechanistic understanding of how FDCs contribute to early HIV colonization of lymphoid tissues and helps resolve discrepancies in virus appearance timing between blood and lymph node.

Results, Conclusions, and Discussions:: In the absence of FDCs, the HIV model predicted a ~30-day delay in viral appearance in both blood and lymph node, which is inconsistent with experimental data. Upon integrating FDCs into the spatial model, viral presence in the lymph node occurred within ~10 days—substantially reducing the delay and aligning the model with observed dissemination timelines.

The inclusion of FDCs and spatial dynamics bridges the gap between experimental observations and computational predictions. These results underscore the critical role of FDCs in early HIV seeding of lymphoid tissues and enhance the biological fidelity of current HIV modeling frameworks. This approach offers valuable insights into the mechanisms of viral persistence and may inform future therapeutic strategies aimed at targeting lymphoid reservoirs.

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